Identification of Ebsulfur Analogues with Broad‐Spectrum Antifungal Activity

Abstract

Invasive fungal infections are on the rise due to an increased population of critically ill patients as a result of HIV infections, chemotherapies, and organ transplantations. Current antifungal drugs are helpful, but insufficient in addressing the problem of drug-resistant fungal infections. Thus, there is a growing need for novel antimycotics that are safe and effective. The ebselen scaffold has been evaluated in clinical trials and has been shown to be safe in humans. This makes ebselen an attractive scaffold for facile translation from bench to bedside. We have recently reported a library of ebselen-inspired ebsulfur analogues with antibacterial properties, but their antifungal activity has not been characterized. Herein, we repurposed ebselen, ebsulfur, and 32 additional ebsulfur analogues as antifungal agents by evaluating their antifungal activity against a panel of 13 clinically relevant fungal strains. The effect of induction of reactive oxygen species (ROS) by three of these compounds was evaluated. Their hemolytic and cytotoxicity activities were also determined using mouse erythrocytes and mammalian cells. The MIC values of these compounds were in the ranges of 0.02–12.5 µg/mL against the fungal strains tested. Notably, yeast cells treated with our compounds showed the accumulation of ROS, which may further contribute to the growth inhibitory effect against fungi. This study provides new lead compounds for the development of antimycotic agents.

Bis(N-amidinohydrazones) and N-(amidino)-N′-aryl-bishydrazones: New classes of antibacterial/antifungal agents

“…30-32 Universally, eukaryotic cells produce basal amount of ROS in mitochondria as a byproduct of cellular metabolism. In response, the cellular enzymatic antioxidants, including superoxide dismutase and glutathione peroxidase, scavenge ROS in cells.…”

Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells

“…In an intensive search for non-antifungal drugs exhibiting antifungal activity, we and others [22–24] demonstrated that ebselen possesses potent broad-spectrum fungicidal activity against Candida and Cryptococcus spp with the MIC values ranging from 0.5 to 2 μg/ml. Although, its antifungal activity has been reported before, the antifungal mechanism of action and in vivo efficacy of ebselen remains unclear with several potential targets proposed [17,22–24]. In the present study, we demonstrated that ebselen reduces GSH concentration in yeast cells leading to dysregulation of redox homeostasis.…”

“…This finding is in agreement with a recent study by Ngo et. al that demonstrated ebselen treatment induces ROS in Candida albicans [22]. In addition, Azad et.…”

“…Recently, we demonstrated that ebselen exerts its antibacterial activity through the inhibition of protein synthesis in bacteria [20,21]. Ebselen has also been shown to possess potent antifungal activity, though different molecular targets have been proposed [22–24]. Studies by Billack et.al and Chan et.al demonstrated that ebselen inhibits the plasma membrane H(+)-ATPase pump (Pma1p) in yeast [23,24].…”

Novel fluconazole derivatives with promising antifungal activity

“…21–27 There are examples of 2,4-difuoro-2-(1 H -1,2,4-triazo-1-yl)acetophenone analogues with linear C 5 –C 8 alkyl chains 25 and of an n -alkylated ebsulfur derivative with a linear C 5 alkyl chain, which displayed strong antifungal activity. 24 Similarly, examples of aminoglycosides ( e.g. , kanamycin B (KANB) and tobramycin (TOB)) with linear alkyl chains with 12 and 14 carbons (C 12 and C 14 ) displaying antifungal activity were also reported.…”